Airway Epithelial Expression Quantitative Trait Loci Reveal Genes Underlying Asthma and Other Airway Diseases

Abstract

Genome-wide association studies (GWASs) have identified loci that are robustly associated with asthma and related phenotypes; however, the molecular mechanisms underlying these associations need to be explored. The most relevant tissues to study the functional consequences of asthma are the airways. We used publically available data to derive expression quantitative trait loci (eQTLs) for human epithelial cells from small and large airways and applied the eQTLs in the interpretation of GWAS results of asthma and related phenotypes. For the small airways (n = 105), we discovered 660 eQTLs at a 10% false discovery rate (FDR), among which 315 eQTLs were not previously reported in a large-scale eQTL study of whole lung tissue. A large fraction of the identified eQTLs is supported by data from Encyclopedia of DNA Elements (ENCODE) showing that the eQTLs reside in regulatory elements (57.5 and 67.6% of cis-and trans-eQTLs, respectively). Published pulmonary GWAS hits were enriched as airway epithelial eQTLs (9.2-fold). Further, genes regulated by asthma GWAS loci in epithelium are significantly enriched in immune response pathways, such as IL-4 signaling (FDR, 5.2 3 10 24 ). The airway epithelial eQTLs described in this study are complementary to previously reported lung eQTLs and represent a powerful resource to link GWAS-associated variants to their regulatory function and thus elucidate the molecular mechanisms underlying asthma and airway-related conditions.

A cellular census of healthy lung and asthmatic airway wall identifies novel cell states in health and disease

“…Hence, we postulate that mucous ciliated cells represent a transition cell state in the ciliated lineage - induced by IL4/IL13 signalling - leading to a mucous cell phenotype which contributes to mucous cell metaplasia in asthma 24 . Similar to goblet cells, mucous ciliated cells express asthma genes such as CST1 28 and POSTN (Figure 3D), indicating that these cells also contribute to airway inflammation and remodelling.…”

Identification of STOML2 as a putative novel asthma risk gene associated with IL6R

“…Specifically, for each gene X (e.g. BCL6 ) that is associated with IL6R , we (1) extracted summary association statistics (effect, risk allele, P -value) for SNPs within 1 Mb of the gene boundaries from the Ferreira et al GWAS (22), which included 6,685 asthmatics and 14,091 controls; (2) selected the SNP with the most significant association with asthma (amongst those with P <0.05) in that 1 Mb interval; (3) identified all genes whose expression was previously reported to associate (typically, but not always, with FDR < 0.05 imposed by the original study) with this SNP (or a proxy, r 2 >0.8) in 11 published GWAS of gene expression levels conducted in cells/tissues relevant to asthma (15, 23-32); and (4) retained that SNP for further analysis if one of the genes known to be regulated by this SNP was also gene X (i.e. BCL6 ).…”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…In addition to associations with FEV1 and FEV1/FVC, unsurprisingly these SNPs have also been associated with COPD susceptibility (Table 5) (Brehm et al, 2011;Castaldi et al, 2011;W. Chen et al, 2015;Cho et al, 2010;Cho et al, 2012;Kim et al, 2014;Pillai et al, 2009;Soler Artigas, Wain, et al, 2011;Van Durme et al, 2010;Wilk et al, 2012).…”

“…For example, our research group prioritized genes at locus 4q24 previously associated with the lung function measure FEV1 and risk of COPD by identifying eQTL SNPs in a range of datasets generated in lymphoblastoid cell line, liver and brain tissue (Obeidat et al, 2013 (Hao et al, 2012;Obeidat et al, 2015), blood cells (Westra et al, 2013) and airway epithelial cells (X. Li et al, 2015;Luo et al, 2015). The diversity of human tissues and cells and cohort sizes with eQTL data available will continue to expand.…”